Selective dehalogenation of certain halogenated ketones



Patented Jan. 26, 1954 SELECTIVE .DEHALOGENATION OF CERTAIN HALOGENATED KETONES Percy L. Julian, Maywood, and William J. Karpel,

Chicago, 111., assignors to The Glidden Company, Cleveland, Ohio, a. corporation of Ohio No Drawing. Application September 17, 1949,

Serial No. 116,415 1 10 Claims. (Cl. 260- 397.4)

The present invention relates to a process useful in the production of steroid compounds having a 17a-hydroxy group, and particularly relates to a process for producing l7-bromo-20- keto pregnenes andpregnanes.

In a broad program for the preparation of 17a-hydroxy-20-keto and 17a-hydroxy20-hydroxy pregnenes and pregnanes (I), it is desirable to have a clean-cut route to 17-bromo-20- keto pregnenes and pregnanes (II). These latter are excellent precursors for the corresponding A -20-keto compounds (III), which, themselves, are readily converted into the appropriate 16,1'7-oxido-20-keto pregnenes and pregnanes (IV).

(I) (II) (III) (IV) The procedures hitherto described in the literature, Marker et al., J. AC. 8., 64, 1276 (1942) Marker and Crooks, U. S, .Patent 2,369,065; Inhofien, U. S. Patent 2,409,043; Plattner et-al., Helv. 31, 603 (1948), leave much to be desired in the matter of obtaining pure 17-brom0-20- keto pregnenes and pregnanes. Indeed, even where these substances have been reported to have been isolated, the yields are poor, and we find that these poor yields are attributable to the contamination of the l'l-bromo compounds with 17,2l-dibromo compounds and 17,21,21-tribromo compounds. No clean-cut method has hitherto been recorded in the literature for the removal from this mixture of the greatest contaminant; namely, the 17,21-dibromo compounds, yet we find that 17,21-dibromo-20-keto pregnenes and pregnanes always arise on the bromination of 20-keto pregnenes and pregnanes with free bromine, no matter what the quantities or the conditions. It has been claimed, for example, by Markeret al., J. A; C. S., 64-, 210 (1942) that pregnanolone gives 17-.bromo pregnanolone almost exclusively on treatment with free bromine. In our hands this'l'l-bromo pregnanolone was impure and was found to be contaminated with its 17,2l-dibromo' derivative.

It is accordingly, therefore, an object of the present invention to-provide'a method for preparing substantially pure lI-bromo-20-keto pregnenes and pregnanes. V

Itisanother object of the invention to provide a -m'ethod for the preparation of17-bromo-20- keto pregnenes and pregnanes free from con tamination by 17,21-dibromo-20gketo pregnenes and 'pregnanes. I

Still another object of the invention is to provide a method for the conversion of 17.21 -dibromo-20-keto pregnenes and pregnanes into the corresponding 17-bromo-20'-k-eto pregnenes and pregnanes.

Yet another object of the invention is to pro-1 vide a method for converting 17,21--dibro1no-20- keto pregnenes and pregnanes into the corresponding l7-bromo-20-keto derivatives in the presence of the latter.

A still further object of the present invention is to provide a method for the removal of 17,21,21- tribr-omo-ZO-keto pregnenes and pregnanes from the corresponding l7-bromo-20- keto derivativesi Other objects will'be apparent to those-skilled in the art.

It has been found that on treatment of 5,6,17,21 tetrabromopregnane-3 3-ol-20-one (V), or its acetate, with an amount of sodium iodide corresponding to greater than three moles of the latter per mole of the former, the tetrabromopregnane is converted almost quantitatively into 17-br0mo-20-iodo-5-pregnene-3fi-ol-20-one (VI), or its acetate. Marker et al., J. A. C. S., 64, 1276 (1942) treated the tetrabrcmopregnane with two moles of sodium iodide and thought their product was the 17,21-dibromopregnene (VII). Marker et al. claim this product in U. S. Patent 2,369,065; Repetition of the work of Marker et al. has shown that their product is a mixture of several sub.- stances, among which may be someof VlIand in which there is definitely a considerable portion of VI,'and probably some of thel'l-bromo compound as -well as some 01 the 17,21-2l-tribromo compound.

Inhoffen, U. S. Patent 2,409,043, 1946,'.treated the tetrabromopregnane (V) with an amount of sodium iodide that calculates out. to be 3.6 moles per mole of the tetrabromo compoundand writes his product as the 17,21-dibromo compound (VII).

ICHzBr Repetition by us of Inhofiens experiments shows that the compound he claimed to be VII is almost pure VI.

What is significant for this invention in the above cited errors in the work of Inhoifen and Marker et a1. is that the discovery of these errors and, therefore, the discovery of this selective reactivity with sodium iodide has led us to a selective dehalogenation of the pregnenes and pregnanes in question, and we have found that pregnenes and pregnanes of the type represented by Formula VI, namely, the 17 -bromo-2l-iodo-20- keto pregnenes and pregnanes, are smoothly reduced to the 17-bromo-ZO-keto-pregnenes and pregnanes of the type II on treatment with sodium bisulfite. Thus, the 21-iodo group in 20- keto pregnenes and pregnanes of the type VI is smoothly replaced by hydrogen on stirring a solution of VI in an organic solvent with an aqueous solution of sodium bisulfite without affecting the 17-bromo group. Therefore, a novel and clean-cut method of selective dehalogenation of compounds like VII has been achieved.

Moreover, since, as stated above, the bromination of 20-keto pregnenes and pregnanes leads to a mixture of substances containing II, V and VIII, a method has been achieved which converts Br Ce I (VIII) all of V into II even in the presence of considerable quantities of II. Further, it has been found that the solubility of VIlI diifers so greatly EXAMPLE I Preparation of 17-bromo-21-iodo-5-pregnene- 3p-0l-20-one acetate A solution of 96.4 g. pregnenolone acetate in 1900 cc. glacial acetic acid is treated with 1 mole bromine in acetic acid at 20 0., followed by 1 cc.

32% HBr in acetic acid and then slowly with 2 moles bromine in acetic acid at room tempera- After the addition of bromine is comutes to complete the reaction, and then cooled to room temperature, filtered and washed with ether. The yield of 5,6,17,2l-tetrabromopregnane-3 3-ol-20-one acetate is 151.3 g., M. P. 176- 177 C. dec. Anal.Calc. for C23H32O3B1'42 C=40.85; H=4.77. Found: 0:40.43; H=4.85.

A solution of 17.0 g. 5,6,17,21-tetrabromopregnane-3p-ol-20-one acetate in 205 cc. benzene is treated with a solution of 45 g. sodium iodide in 205 cc. ethano1 at room temperature for 24 hours. The reaction mixture is diluted with water and extracted with ether. The ethereal benzene solution is washed with 1% sodium hydroxide solution to remove free iodine, washed with water to neutrality and dried over sodium sulfate. Upon concentrating the solution under vacuo to a volume of 40 cc. and diluting with cc. warm methanol, there is obtained 10.3 g. 17-bromo-2liodo-5-pregnene-3fi-ol-20-one acetate, M. P. 154 C. dec. Anal.Calc. for C23I-I32O3BrI: C=49.03; H=5.74. Found: 0:48.83; H=5.72.

EXAMPLE I[ Reduction of 17-bromo-21-iodo-5-pregnene-3B- ol-20-one acetate with sodium bisulfite A solution of 5.9 g. 17-bromo-21-iodo-5-pregnene-3B-ol-20-one acetate in 50 cc. benzene and 50 cc. ether is shaken with 30 cc. 10% aqueous sodium bisulfite solution. Free iodine is liberated in the ether benzene layer, whereupon the mixture is shaken to remove the iodine. As iodine is again liberated the mixture is again shaken. This procedure is repeated until no more iodine is liberated. From 15 to 30 minutes is required to complete the reduction. The ethereal solution is washed with 1% aqueous sodium carbonate solution, with water to neutrality and then dried over sodium sulfate. The solution is concentrated under vacuo to 10 cc. volume and diluted with 25 cc. warm methanol. There is .obtained 3.8 g., 17-bromo-5-pregnene-3p-ol-20- one acetate, M. P. 134-140 C.

Crystallization from methanol raises the melting point to 145-146 C. Anal.Calc. for C23H3303B1': 0:63.15; H=7.6. Found: C=62.77; H=7.48.

EXAMPLE IlI 5,1G-pregnadiene-tfl-ol-ZO-one acetate from 17- bromo-5-pregnene-3p-ol-20-one acetate A solution of 18.0 g. 17-bromo-5-pregnene 3pol-20-one acetate in cc. collidine is refluxed for 6 hours. The cooled mixture is diluted with ether and extracted with 15% aqueous hydrochloric acid to removethe collidine and then washed with water to neutrality. The ethereal solution is dried over sodium sulfate and concentrated to the point of crystallization and then chilled and filtered. There is obtained 10.8 g. 5,16-pregnadiene-3p-ol-20-one acetate, M. P. 172-174 C.

'EXAMPLEIV Preparation of 17-bromo-S-pregnene-3p-ol-20- one acetate A solution of 151.3 g. 5,6,17,21-tetrabromopregnane-Bfl-ol-ZO-one acetate in 1800 cc. benzene is treated with a solution of 400 g; sodium iodide in 1800 cc. ethanol at room' temperature for 24 hours. The reaction mixture is diluted with water and extracted with ether. The ethereal benzene solution is washed with 1% sodium hydroxide solution to remove free iodine and then washed with water to neutrality. The ethereal benzene solution is shaken with 300- cc. sodium bisulfite solution. Free iodine is liberated in the ether-benzene layer; whereupon the mixture is again shaken. This procedure is repeated until no more iodine is liberated. The ethereal solution is washed with 1% aqueoussodium carbonate solution, with water to neutrality and then dried. over sodium sulfate. The solution is concentrated under vacuum'to 150 cc. total volume and diluted with 265 cc. warm methanol. There is obtained 84 g. of crude l7-bromo-5- pregnene-3Bol-20-one acetate, P. HIP-139.

EXAMPLE V Remooal of high-1n.eltiug I 7,21',Z1=-tribromomegnenol'one acetate One gram of crude l'l-bromo pregnenolone acetate is taken up in 5 cc. hexane and allowed to crystallize at room temperature, whereupon 0.1 g. hard prisms. M 1?. 190, separated. Anal. Calc. for CzaI-ImOsBra: 0:46.41; H:.5.25. Found: 0:46.64; H:5.39. The hexane liquor is concentrated and crystallized. from methanol. There is obtained 0.8 g. 17-bromo pregnenolone acetate, M. P. 143

EXAMPLE VI Repetition of Markers experiment on bro mination of pregnenolone acetate and treatment with 2 moles sodium iodide A solution of 0.872 g. sodium iodide (2.0 moles) in 20 cc. ethanol was added to a boiling suspension of 2.9 g. 5,6,l7,2l-tetrabromopregnenolone acetate in 300 cc. ethanol and refluxed for .1 hour. The solution was cooled, diluted with water and extracted with ether. The ethereal solution was washed with 5% sodium thiosulfate solution to remove free iodine and then washed with water. The colorless ethereal solution was divided into two equal parts. Part I was dried and concentrated under vacuum to 0.7 g. solid residue and crystallized from ether-methanol yielding 0.47 g., M. P. 100-110 C. A portion of this material was fused with sodium. and when qualitatively tested for iodine via the sodium. nitrite test showed that iodine was present. A portion was recrystallized 3 times from other methanol, melted at 148 and did not show a depression in melting point when admixed with 17-bromo-21-iodo pregnenolone acetate.

Part II of the original ethereal solution was shaken with 10% aqueous sodium bisulfite solution. Free iodine was liberated in ethereallayer.

This was repeated 3 times until no more iodine:

was liberated. The solution was washed with. 1% aqueous sodium carbonate solution,.with water to neutrality, and then dried and concentrated to a solid residue yielding 0.33 g., M. P. 106-115".

EXAMPLE VII Repetition of Inhofiens emperiment A solution of 1.0 'g. tetrabromopregnenolone acetate in cc. benzene was treated with a solution of 0.8 g. sodium iodide (3.6 moles) and refluxed for 2 hours. The solution was cooled, diluted with water and extracted with ether and finally washed with sodium thiosulfate solution and the water; Upon concentrating under vacuum and crystallizin-g, there is obtained 0.6 g. material, M. P. 130-132, dec. This was recrystallized 3 times and then melted at .146? deo. and didnot show a depression in meltin'gpoint when admixed with 17-bromo-2l iodo pregnenolone acetate. The optical rotation of this ma- A solution. of. 2.5 g. allopregnanol'one. acetate in '15 cc. glacial acetic acid containing 2; drops 32% HBr is treated SIOWIMRK 25 -30 C. with lid-cant: :a l Masolutiorr-oi bromine in acetic acid; After thesolution has'stoodiat 30 ,for 15- minutes, water is added slowly until. precipitationiscomplete The crystallinermass is filtered, washed with water and dried im a. hotair oven. The: crude. bromination product.- is crystallized from acetone-methanol yielding 2.9 g., M. P. 1.65 -1'20". i

To asolutionoi 3.0 g1} of the thus formed 11,2l-dibromoallopregnanolone. in36 cc. benzene is added a solution. of 5.1;. sodium. iodide in 3.6- cc. ethanol. and the. mixture allowed to stand at room. temperature for 24 hours. The. reaction mixture is 'dilutedwith water and extracted with ether; The ethereal benzene solution is washed witn 1% sodium hydroxide solution to remove free iodine, themwashed with water to neutrality. The Ir'Z-bromo 21l iodo. allopregnanolone acetate, M. P. 136-l38 dec. need not be isolated and can be reduced directly. The ethereal-benzene solution is shaken with 20 cc. of 1.0% aqueoussodium bisulfite solution. Free iodine is liberated in. the ether-benzene layer, whereuponthe. mixture is ag'ain shaken. The procedure isrepeated. until no more iodine is liberated. The solutionis then washed with 1% aqueous. sodium. carbonate solution and with watertoneutrality and then dried and concentrated. The ,residue is taken up in ether and crystallized. There is obtained. 0.9 g. M. P. 197 -199- dec. ot a tribromo derivative by-product. Calc. for C'zsHazOeBra: 0:46.33; 11:541. Found: 0:46.51 H=5.55.

From the liquor there is obtained 1.2 g. M. P. L12-l15 C., l'l-bromo-allopregnanolone acetate. Crystallization from methanol raises the melting point to 128 C.

A-solution of 0.4 g. -17-bromo-al1opregnanolone acetate in 4 cc. coll-idine is refluxed for 3 hours. The cooled mixture is diluted. with ether and extracted with 15% aqueous hydrochloric acid to remove collidine and then washed with water to neutrality. The ethereal solution is dried. concentrated and petroleum ether is added. There is readily." obtainedoz g. of l6.-allopregnenoloneacetate, M. P.1158-". Crystallized from acetone. it melts at 162.

The preparation 3 ,1i2-diaeet0ry-16- :pregnene-lZfl-one To a solution of 1.0 g. of 3a-,l; 2a-diacetoxypregnaneafl-onein -8 cc. of acetic acid, containing one drop of -32 in" acetic acid and a few crystals of anhydrous aluminum chloride, there was added, dropwise, 0.42 g. of bromine in 4 cc. of acetic acid at room temperature. A'fter complete absorption? of bromine, the solutionswas poured into water and the white solid separated by filtration. Afiter drying, the washed solid. weighed 1.16 g. material was dissolved in '13 cc. otbenzene and treatedwith a solution of 1.0 2. of sodium iodide at room temperature for twenty-four hours. The iodineabsorption maximum at 240 m typical of such an in-unsaturated ketone.

It can readily be seen from theioregoing that a clean-cut procedure is provided for the pro duction of 17-bromo-20-keto pregnenes and pregnanes. It'will be understood, however, that many variations maybe made incarrying out the invention. As pointed outt'he procedures of both Marker and Inh'offen produce some 17-'-' bromo-Zl-iodo compound but it is preferable to use sufiicient sodium iodide to reduceany bro'mo groups present reducible by sodium iodide, 'as well as to replace the 21-bromine atom by-iodine. As indicated, however, the l7-tertiary bromo group is not affected by the sodium iodide. It will, of

v course, be understood that in any case the l!- bromo-2 1iodo-20-keto compounds,- whether in admixture or otherwise, may be treated with 'sodium bisulfite to replace the '21-iodo group with hydrogen. Where insufficient bromine has been initially used to'brominate all of the starting'material, it may, of course, be recovered.

The invention is obviously not limited to the treatment of the specific steroids mentioned in the examples. Thus, if desired, pregnene and pregnenes having the 3-keto group may be employed. Also pregnenes and pregnenes, such as those having oxygenated'functions at other positions in the molecule, such as at the 11 or 12 posl tions, may be treated in accordance with the present invention.

It is not necessary to trat the acetate where the 3-hydroxy compounds'are employed. How'- ever, bromination in acetic acidis a convenient procedure and this procedure inherently produces acetylation. Bromination in chloroform may be carried out, however, on the free hydr xy compounds. Also if the acetate group is undesirable, other esters may-be formed, such as the benzoate, etc. and the bromination carried out in acetic acid.

The 17-bromo-20'-keto compounds produced by the present invention may bereadily dehy drobrominated to yield compounds containing a 16-17 double bond; which, may then be readily converted to the 16,1'7-oxido-compounds. The oxido compounds'upon' treatmentwith lithium aluminum hydride, as set forth in co-pcnding application Serial No. 93,638,'filed May 16, 1949, vielcl compounds possessing l'l a -hydroxy and zil hydroxy groups. If 17ahydroXy.-20 lretocomf pounds are desired, the 20 -ketogroup'may readily. be protected during the reduction of the oxide group as set forth in co-pending application Serial No. 108,658, filed August 4,1949. Since many of the active cortical hormones possess the l'ia-hydroxy group, it is readily seen-that the present invention is valuable in the partial synthesis of such compounds from the more abun:

bisulfite treatment.

dant steroid compoundsywhich; do not possess this group. v I

, Having described the invention, what is claimed 1. The process which comprises treating a steroid compound selected from the class consisting of l'l-bromo-21-iodo-20-keto pregnenes and pregnenes with sodium bisulfite.

--2. The process which comprises treating 17- bromo-21-iodo-20-keto pregnenes with sodium bisulfite. I o

3. The process of claim 2 in which the double bond in the pregnene involves the number 5 carbon atom.

4. The process which comprises treating an acetate of a 17-bromo-2l-iodo-5-pregnene-3ol- -20-one with sodium bisulfite.,

5. The process which comprises treating 1'7- bromo-21-iodo-5-pregnene 3 ol-20-one acetate with sodium bisulfite.

6. The process which comprises treating an acetate of a l7-bromo-2l-iodo-pregnane-S-ol-ZO- one with sodium bisulfite.

7.,The process which comprises treating a steroid compound selected from the class consisting of 20-keto pregnenes and pregnanes with sufficient bromine to form a l'7-bromo-2l-bromo 20-lgeto compound, and treating the resulting 17- bromo-21-bromo-20-keto compound with sufficient sodium iodide to replace the 21-bromine atom with iodine, and treating the resulting 21- iodo compound with sodium bisulfite.

'8. The process which comprises treating 'a steroid compound selected from the class consisting of '20-keto pregnenes and pregnanes with sufiicient bromine to form a 17 -bromo-21-bromo- 20-keto compound, treating the resulting mixture of brominated steroids with suflicient sodium iodide to replace the 2l-bromine atom with iodine, treating the mixture containing the 21-iodo derivative with sodium bisulfite, and recovering the resulting 17-bromo-20-keto steroid from the mixture.

9. The process which comprises treating a mixture containing 17-bromo-21-bromo-2U-keto and 17 bromo-20-keto derivatives of a steroid selected from the class consisting of pregnenes and pregnanes with sufiicient sodium iodide to replace the 21-bromine atom with iodine, treating the resulting mixture containing the 2l-iodo compound with sodium bisulfite, and then recovering il-bromo-20-ke'to steroid from the resulting mlxure.

10. The process which comprises treating a mixture containing 17-bromo-2l-bromo-ZO-keto, 17-bromo-20-keto and l7-bromo-21,2l-dibromo- 20-keto derivatives of a steroid selected from the class consisting of pregnenes and pregnanes with sufiicient sodium iodide to replace the bromine of the 1'7-bromo-21-bromo-derivative by iodine, treating the resulting mixture with sodium bisulfite and then fractionally crystallizing any 1'?- bromo-21,21-dibromo-20-keto compound from a solution of the mixture resulting from the sodium PERCY L. JULIAN. h WILLIAM J. KARPEL. References Cited in the file of this patent UNITED STATES PATENTS Number Name Date 2, Marker Feb. 6, 1945 

1. THE PROCESS WHICH COMPRISES TREATING A STEROID COMPOUND SELECTED FROM THE CLASS CONSISTING OF 17-BROMO-21-IODO-20-KETO PREGNENES AND PREGNANES WITH SODIUM BISULFITE. 